Membranes steroid receptors

Steroid hormones act in a different manner from most hormones we have considered. In many cases, they do not bind to plasma membrane receptors, but rather pass easily across the plasma membrane. Steroids may bind directly to receptors in the nucleus or may bind to cytosolic steroid hormone receptors, which then enter the nucleus. In the nucleus, the hormone-receptor complex binds directly to specific nucleotide sequences in DNA, increasing transcription of DNA to RNA (Chapters 31 and 34). 

Most receptors (a notable exception being the steroid receptors that influence DNA transcription) are located on the cell surface, and purified cell membranes are thus an obvious choice of preparation. When a tissue is homogenized, however, any membrane fraction isolated may well contain membranes from intracellular organelles in addition to cell membranes from all the cell types present in the tissue. Thus, brain membranes will contain membranes not only from neurons but... 

The cellular mechanism of action of hydrocortisone, a glucocorticoid, is also related to proteins but not by the enhancement of cAMP production. Hydrocortisone is transported by simple diffusion across the membrane of the cell into the cytoplasm and binds to a specific receptor The steroid-receptor complex is activated and enters the nucleus, where it regulates transcription of specific gene sequences into ribonucleic acid (RNA). Eventually, messenger RNA (mRNA) is translated to form specific proteins in the cytoplasm that are involved in the steroid-induced cellular response. 

At the same time, there is evidence for membrane-associated steroid receptors that are coupled to second messenger systems (see below). 

Levin ER (2002) Cellular functions of plasma membrane estrogen receptors. Steroids 67 471... 

Receptors are proteins or glycoproteins found either on the surface of the target cell or located within the cell interior. The surface receptors engage peptide hormones which, being hydrophilic, do not traverse the fatty plasma membrane intracellular receptors combine specifically with particular steroids or tri-iodothyronine, T3. 

All corticosteroids have the same general mechanism of action they traverse cell membranes and bind to a specific cytoplasmic receptor. The steroid-receptor complex translocates to the cell nucleus, where it attaches to nuclear binding sites and initiates synthesis of messenger ribonucleic acid (mRNA). The novel proteins that are formed may exert a variety of effects on cellular functions. The precise mechanisms whereby the corticosteroids exert their therapeutic benefit in asthma remain unclear, although the benefit is likely to be due to several actions rather than one specific action and is related to their ability to inhibit inflammatory processes. At the molecular level, corticosteroids regulate the transcription of a number of genes, including those for several cytokines. 

One of the most unique and powerful features of steroid hormones is the nature of the steroid receptor. Unlike most other hormones or drugs, which target protein receptors usually embedded in membranes, steroids target the genes themselves, buried deep within the nucleus of the cell. 

Mammalian cells acquire cholesterol either by de novo synthesis from acetyl-coen-zyme A (CoA) or via the low-density lipoprotein (LDL)-receptor-mediated uptake of LDL particles that contain cholesterol esterified with long-chain fatty acids. These LDL cholesterol esters are subsequently hydrolyzed in lysosomes, after which free cholesterol molecules become available for synthesis of membranes, steroid hormones, bile acids, or oxysterols [1]. 

Two other, faster-acting mechanisms produce some of the effects of steroids. Progesterone triggers a rapid drop in [cAMP], mediated by a plasma membrane receptor, and binding of progesterone to the classic soluble steroid receptor activates a MAPK cascade. 

Figure 17.4 Intracellular steroid receptor activation by hormone ligands, (a) Steroid hormones diffuse across the cell membrane into the cell. (b) Steroid hormone receptors in the basal state bound to accessory proteins, (c) Steroid hormones bind to receptors and accessory proteins are dissociated from the receptors. (d) Hormone receptor complexes dimerize. (e) Dimer complexes enter the nucleus and initiate transcription of responsive genes.

As indicated in Table 9.1, the endocrine hormones can be divided into two major chemical classes (1) the peptides and amino acid derivatives and (2) the cholesterol-based steroid compounds. In general, the former are believed to interact primarily with membrane-associated receptors, while the latter are more lipophilic and are able to gain entrance into target cells. In any event, overactive or underactive endocrine... 

In addition to the actions mediated by intracellular receptors, steroid hormones also demonstrate certain rapid (occurring within seconds) actions, which appear to be mediated by membrane effects/receptors this is true for vertebrate [114] and invertebrate [115] steroids. One presumes that the SAR studies for ecdysteroids which have been performed to date are predominantly determined by interaction of ecdysteroids with nuclear receptors, but one should bear in mind that in certain assay systems the... 

Steroid Receptors. Steroid receptors such as estrogen, progesterone, and androgen receptors are overexpressed in breast, ovarian, and prostate cancers. Estrogen and progesterone receptors are present in about 65% of human breast cancers. The presence or absence of these receptors in cases of breast carcinoma assists the determination of the therapeutic strategy (hormonal or chemical) that is likely to be effective. The successful Tc complex must cross the membrane lipid bilayer of the cell, and thus, the size and lipophilicity of the complex must be balanced with receptorbinding affinity. 

DNA. Steroid receptors have been reported in mitochondria (17) and cell membranes, although it is not yet clear whether all of these receptors are the same as the intracellular steroid receptors (16, 18-22 vs. 23). Some of the membrane-bound receptors for steroids are G protein-coupled receptors (24—27). A recent report suggests that membrane-bound steroid receptors can interact with, and augment the transcriptional activity of, the intracellular receptors (24). Finally, steroids can bind to nonreceptor molecules such as enzymes and transport proteins (see above), which may have yet undiscovered consequences. 

In contrast to most receptors, most ligand-free steroid receptors are not membrane bound. They can be cytoplasmic or nuclear, depending on the receptor and the time scale. At a given instant, ERs are mostly nuclear, like the nuclear receptors. Eor the other receptors, the amount of nuclear localization is PR > MR > AR and GR. However, the dynamic picture is that receptors are shuttling back and forth across the nuclear membrane (53)... 

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